1. Field of the Invention
The present invention relates to processes for the preparation of carbapenem-type antibacterial agents having a 1-alkylpyrrolidine structure which exhibit excellent antibacterial activity, to 5-alkyl-2-thia-5-azabicyclo[2.2.1]heptan-3-ones or salts thereof which are useful as synthetic intermediates, and to processes for the preparation thereof.
2. Background Information
Various carbapenem-type antibacterial agents having a 1-alkylpyrrolidine structure which exhibit excellent antibacterial activity are known. For example, Japanese Patent Application Publication No. Hei 11-071277 discloses carbapenem-type antibacterial agents having a 1-alkylpyrrolidine structure and a process for the preparation thereof. But, while the process described in the publication involves combining the three parts of the structure of the carbapenem-type antibacterial agent which is the desired compound in a stepwise manner, the process for the preparation of a carbapenem-type antibacterial agent having a 1-alkylpyrrolidine structure described in the present invention differs in that the three parts of the structure are combined continuously in one step, that is, in a one-pot synthesis.
Also, Heterocycles, 41, 147 (1995) discloses carbapenem-type antibacterial agents (meropenem) having a pyrrolidine structure that have no substituent on the nitrogen atom and a process for the preparation thereof. Then, the starting compound used for the process described in the literature, and the starting compound used for the process for the preparation of a carbapenem-type antibacterial agent having a 1-alkylpyrrolidine structure described in the present invention, have in common the fact that they are both 2-thia-5-azabicyclo[2.2.1]heptan-3-one derivatives. But, in the starting compound of the process described in the literature, the nucleophilicity of the nitrogen atom is decreased because of the presence on the nitrogen atom of a p-nitrobenzyloxycarbonyl group (a carbonyl-type protecting group), thereby suppressing side reactions. Whereas, in the starting compound of the process of the present invention, the nitrogen atom in the structure is nucleophilic, and the chemical properties of the starting compound of the present invention are different from those of the starting compound described in the above literature, so there was a concern about side reactions or decrease in yield accompanying side reactions. Furthermore, the scale of the synthetic example described in the literature is very small (the yield from the starting material was 69%, and the process afforded 315 mg of product), so it is not clear whether or not the process for the preparation of a carbapenem-type antibacterial agent described in the literature could be applied to the large scale production of a carbapenem-type antibacterial agent having a 1-alkylpyrrolidine structure described in the present invention.
Also, various processes for the preparation of 2-thia-5-azabicyclo[2.2.1]heptan-3-one derivatives are known. For example, J. Org. Chem., 46, 4182 (1981) and Chem. Pharm. Bull., 20, 543 (1972) disclose compounds protected with an acetyl group at the nitrogen atom of 2-thia-5-azabicyclo[2.2.1]heptan-3-one. But the method described in the literature is not suitable for large scale production, because it uses N,N′-dicyclohexylcarbodiimide, which is a condensation agent accompanied by a serious problem of treatment after the intramolecular cyclization step.
Carbapenem-type antibacterial agents have superior antibacterial activity, while they generally have a complex chemical structure. Accordingly, concerning the carbapenem-type antibacterial agents having a 1-alkylpyrrolidine structure described in the present invention, the construction of cheaper, easier, and highly safe synthetic routes suitable for large scale production has been desired.
Also, the 5-alkyl-2-thia-5-azabicyclo[2.2.1]heptan-3-ones of the present invention are very important intermediate compounds for a synthetic route to carbapenem-type antibacterial agents having a 1-alkylpyrrolidine structure which can achieve the above purpose. A cheaper, easier and highly safe process suitable for large scale production of these compounds has been desired.